Procaine ascorbate preparation



Patented July 20, 1954 PROCAINE ASCORBATE PREPARATION Simon L. Ruskin,New York, N. Y., assignor to Physiological Chemicals Company, NewRochelle, N. Y., a corporation of New York N Drawing. ApplicationOctober 21,. 1950,

Serial No. 191,483

4 Claims.

The present invention relates to the preparation of an improved form ofthe anaesthetic compound procaine and more particularly to thepreparation of procaine ascorbate.

The present application is a continuation-inpart of my co-pendingapplication Ser. No. 528,612, filed March 29, 1944, now Patent No.2,606,903, which is in turn a continuation-in-part of my earlierapplication Serial No. 457,598 filed September 7, 1942, now Patent No.2,419,230.

Procaine is a well known local anaesthetic and is employed in medicinein the form of a salt, usually with an inorganic acid, the hydrochloridebeing the salt most commonly employed. The use of the known procainesalts has, however, been attended with serious disadvantages. Quitefrequently, edema sets in after the anaesthetic has worn off. Ascommonly employed in the form of the hydrochloride, and also as thenitrate, it is quite strongly acid in reaction and consequently causestissue irritation. Procaine is also known to produce convulsions ofvarying degrees of intensity.

It is the general object of the present invention to provide a combinedform of procaine, in which the disadvantages mentioned are overcome.More particularly, it is an object of the invention to provide a salt ofprocaine, which in addition to being free of the irritating anddisturbing efiects encountered with the use of the known procaine salts,is non-toxic and possesses a healing action which has not beenencountered with the procaine salts heretofore employed. Other objectsand advantages of the invention will appear from the more detaileddescription hereinafter.

In accordance with the present invention, I provide the procaine in theform of its ascorbic acid (vitamin C) salt. I have found that procaineascorbate can be employed for local anaesthesia and can be usedintravenously for the control of muscular spastic states, neuralgia,allergic reactions, control of traumatic pains and the like. The salt isnormally neutral in reaction in aqueous solution and is accordinglysubstantially free from tissue irritation.

The favorable therapeutic response of procaine ascorbate is apparentlydue to the fact that it provides a high concentration of the ascorbateradical within the surgical area, so that wound healing is promoted anda firmer union of the surgical areas of the wound results. This isapparently due to the fact that the salt promotes collagen formation.The high level of vitamin C radical which the salt provides directly inthe surgical area cannot be matched by oral administration of vitamin Cbecause the latter is diluted by all the body fluids and is also inlarge part destroyed by intestinal bacteria such as coli, and of thefraction which is absorbed, only a relatively small amount reaches anyparticular part of the body.

I have found further, that procaine ascorbate is a self-detoxifyingpreparation in that the con vulsant properties of the procaine areneutralized by the ascorbyl radical, so that the toxicity of procaine ispractically entirely absent in its ascorbic acid salt.

Procaine ascorbate can be injected intramuscularly in areas to betreated surgically; because it is substantially neutral it can beinjected intravenously in the treatment of arthritis and traumaticinjury. It is also useful intravenously for cardia arrhythmias andsimultaneously corrects disturbances in heart rhythm, while the ascorbicradical acts to improve heart muscle function.

Procaine ascorbate can be marketed in the form of the solid salt to bemixed with sterilized water prior to use, or in the form of a A;% to 2%aqueous solution. If desired, mixtures of a known procaine salt such asthe hydrochloride, nitrate or borate, and an ascorbate of anon-toxicmetal, preferably an alkali or alkaline earth metal, like sodium,potassium and magnesium, can be provided in dry, ampouled form to bemixed with the proper amount of water prior to use. Or procaine base inequimolecular amount with ascorbic acid may similarly be put up inampoule form, in the dry condition.

The following examples illustrate satisfactory ways of preparingprocaine ascorbate by way of illustration and are not to be understoodas indicating the scope of the invention.

Example 1 4.27 g. of ascorbic acid in 1000 cc. of water are stirred with5.73 g. of procaine base. The procaine goes into solution as procaineascorbate. The solution is filtered and ampouled in corn venientamounts, for example 5 cc. of the 1% solution. To the solution there canbe added of sodium bisulphite or of sodium borate as a stabilizer. Thesolution can also be stabilized with 5% dextrose.

For intravenous use, to mg. of the salt in 500 to 1,000 cc. of isotonicaqueous dextrose or saline solution can be administered by slow drip.

Example 2 Equimolecular proportions of procaine base and ascorbic acidin more or less powdered form are 23.6 g. mol) procaine base and 17.6 g.(1 6 mol) ascorbic acid were warmed with about 200 cc. absolute methylalcohol until solution was complete. The resulting solution was thenslow- 1y treated under stirring and cooling with 500 cc. chloroform oracetone. A yellow precipitate was obtained, which hardened on standingovernight in the ice chest. Yield 40 g. or almost quantitative.

The salt procaine ascorbate can be obtained also by evaporation of thesolution obtained according to Examples 1 and 2. The salt can also beprepared by double decomposition, between, for example, procainehydrochloride and a combining proportion of sodium ascorbate. Thesimultaneously produced sodium chloride is unobjectionable and thereforeneed not be removed from the solution or from the solid product obtained on evaporation. This is illustrated by the following example:

Example 4 To an approximately saturated aqueous solution of procainehydrochloride containing 27.3 g. of the salt, there is added aconcentrated aqueous solution of sodium ascorbate containing 20 g. ofsuch salt. The resulting mixture is concentrated and the precipitatedprocaine ascorbate is collected, washed and dried. If desired, the wholereaction mixture can be evaporated to dryness since the sodium chloridethat is present therein is generally unobjectionable. The dried procaineascorbate, with or without sodium chloride, can then be packaged in thedry condition, or the reaction solution itself can be ampouled, or asolution of the separated procaine ascorbate.

The dry solid procaine ascorbate can also be marketed in the form of asuspension in an injectabl-e vegetable oil, like peanut and sesame oils.Thus, mg. can be suspended in 1 cc. of a peanut oil and beeswax mixturewherein the beeswax has the usual proportion to the peanut oil, such as1:4. The suspension is only slowly absorbed and produces a longerlasting effect than the aqueous solution.

Iclaim:

1. Procaine ascorbate.

2. A dry, solid preparation consisting essentially of unreacted procainebase and ascorbic acid in equivalent proportions and adapted, on theaddition of Water, to form procaine ascorbate.

3. A dry, solid preparation consisting essentially of an inorganic acidsalt of procaine and a substantially equimolecular proportion of anon-toxic metal salt of ascorbic acid.

4. A dry mixture of procaine hydrochloride, and a salt of ascorbic acidselected from the group consisting of alkali and alkaline earth metalsalts in equivalent proportions.

References Cited in the file of this patent UNITED STATES PATENTS NumberName Date ,187,467 Stuart Jan. 16, 1940 2,259,492 Ruskin Oct. 21, 19412,294,937 Ruskin Sept. 8, 194-2 OTHER REFERENCES Stanistreet, AustralianJournal of Pharmacy, Sept. 30, 1946, pages 730 to 733.

Ser. No. 373,612, Kok (A. P. C.), published May 11, 1943.

2. A DRY, SOLID PREPARATION CONSISTING ESSENTIALLY OF UNREACTED PROCAINEBASE AND ABSORBIC ACID IN EQUIVALENT PROPORTIONS AND ADAPTED, ON THEADDITION OF WATER, TO FORM PROCAINE ASCORBATE.